Hepatitis B virus causes both acute (transient) and chronic infections. The latter, in particular, create a very high risk of primary hepatocellular carcinoma (PHC). Significant effort has consequently been devoted to finding a cure for chronic infections, since it is believed that if a chronic infection could be cured, especially prior to extensive and prolonged liver damage, the risk of PHC would be greatly reduced. However, with the exception of certain short-term carriers, the treatment protocols that have been used have lacked efficacy, and there is currently no available treatment for the 200 million HBV carriers, worldwide, who have a ca. 25% life-time risk of developing PHC. It has, by now, become clear that our lack of understanding of how hepadnaviruses maintain chronic infections, in vivo, has limited our ability to design widely-applicable anti-hepadnavirus therapies as well as to understand the progression from infection to liver cancer. The widespread belief that hepatocytes are largely nondividing and, therefore, virtually immortal, at least in the absence of toxic or immune injury has, indeed, been a major conceptual barrier in understanding the critical issue of how subclinical infections are naturally resolved, since hepadnaviruses appear highly adapted to productively infect stationary cells and in vivo infections are traditionally viewed to be noncytopathic. The long-term objective of our research is, therefore, to learn more about cell turnover in the normal liver and how it may change in response to a hepadnavirus infection. Through the proposed studies, we expect to achieve the following goals. 1)To determine if infection of hepatocytes significantly reduces the life- span of the infected cells. 2)To determine if hepatocytes are replaced by proliferation of a specialized pool of progenitors within the liver and whether such progenitors are susceptible to hepadnavirus infection. 3)To determine if the cellular immune response to infected hepatocytes causes a rapid repopulation of the liver with "altered" hepatocytes. These experiments will be carried out with Pekin ducks chronically and transiently infected with duck hepatitis B virus and with woodchucks infected with woodchuck hepatitis virus. The results will provide a conceptual basis for the rational design of antiviral therapies together with a description of early changes in the hepadnavirus-infected liver leading to hepatocellular carcinoma.